A solid phase synthesis process based on the phosphoramidite method is widely used to chemically synthesize nucleic acids such as DNA and RNA. In this process, supports for solid phase synthesis supporting a nucleoside that will become the 3′ end of a nucleic acid to be synthesized, previously linked via a cleavable linker (e.g., succinyl group and the like), are filled in a reaction column and applied to an automated nucleic acid synthesizer. Subsequently, according to a synthesis program, (1) deprotection of 5′-OH groups of the nucleoside; (2) coupling of nucleoside phosphoramidite to the 5′-OH group; (3) capping of unreacted 5′-OH groups; and (4) oxidization of the resulting phosphite are repeated in synthesis cycles, whereby a nucleic acid having a desired sequence is synthesized. The nucleic acid synthesized is finally cut out from the carrier for solid phase synthesis by hydrolyzing the cleavable linker with ammonia and the like (e.g., non-patent document 1).
Conventionally, inorganic particles of CPG (Controlled Pore Glass), silica gel and the like have been widely used as supports for solid phase synthesis of nucleic acids. As alternatives therefor, highly crosslinked, non-swellable porous polystyrene particles of improved chemical stability (e.g., patent document 1) and low-crosslinked, swellable porous polystyrene particles that enable the mass synthesis of nucleic acids in the production of nucleic acid pharmaceuticals (e.g., patent document 2) have been developed.
Meanwhile, compared with the synthesis of DNA, the synthesis of RNA encounters a problem of decreased amidite coupling efficiency because of the necessity of the use of a phosphoramidite with a protecting group bound to the 2′-OH group thereof, which results in reduced purity of the RNA obtained. To synthesize RNA while minimizing purity reduction, it is necessary to reduce the amount of nucleoside-linker bound, the nucleoside serving as the starting point of the synthesis on the support for solid phase synthesis, which, however, in turn results in a new problem of a reduced amount synthesized per unit amount of support for solid phase synthesis.